Approximately 33% of adults in the U.S. have used complementary health approaches (NHIS, CDC [4-6]). In doing so, 59 million Americans spend $30.2 billion out-of-pocket/year. The most commonly used complementary approach are natural products ($12.8 billion-almost one fourth of the out-of-pocket amount spent on all prescription drugs combined). Moreover, recent studies have found that CAM use is highly prevalent in this and many other countries with 36-52% of the population using CAM at some time [29]. Despite their frequent use and significant impact in healthcare dollars, scientific research has provided scant evidence for benefit of natural products in cancer therapy. An aqueous extract of wheat germ fermented with Saccharomyces cerevisiae (FWGE) is sold in the U.S. as a dietary supplement (trade name: Avemar). FWGE is cytotoxic to several human cancer cell lines [7-16]; in vivo efficacy has been reported for colorectal carcinoma [17-21], melanoma [22] and squamous cell carcinoma [20] and preliminary clinical data is promising [17, 22, 23]. FWGE reportedly has ?immune-reconstructive? effects [17, 22, 24, 30-32]. These conclusions, however, are mostly based on single-experiment studies devoid of rigorous follow-up. It has been proposed that FWGE activity is based on its content of dimethoxybenzoquinone (DMBQ) [24-27]. However, this has not been proven, and indeed early studies indicated that DMBQ alone cannot be responsible for the immunostimulatory properties of FWGE [24] and may in fact have significant toxicity [33-35]. We have confirmed that FWGE has remarkable anti-tumor activity in NHL models in vivo especially when used in combination with the monoclonal antibody (mAb) rituximab. The efficacy of FWGE was comparable to that of the aggressive R-CHOP regimen, but FWGE had no appreciable toxicity. Our published results suggest that a protein fraction from fermented wheat germ (FWGP), not DMBQ, is responsible for this activity by, at least in part, stimulating natural killer (NK) cell-mediated tumor eradication in vivo [28]. This is a significant observation since abnormal NK cytolytic activity has been described in hematological malignancies [36]. The overall goal of this proposal is to isolate active component(s) in FWGP and to understand its tumoricidal effects by examining activity/toxicity in vivo in canine NHL and ex vivo in humans in anticipation of human clinical trials. Significance for the VA population We have shown that FWGP is effective against NHL, both in vitro and in vivo [28]. NHL is the sixth most common cause of cancer-related death in the United States [1-3]. The fastest growing segment of the population acquiring this disease is elderly males (a substantial segment of the VA patient population). Given this, and the fact that NHL is an agent orange-associated malignancy, the impact on veterans is substantial. We also have substantial preliminary data suggesting that FWGP is effective in pre-clinical models of non- small cell lung carcinoma (NSCLC). NK cell anti-tumor activity in lung cancer is increasingly being recognized as an actionable clinical target [44-47]. While the focus of this proposal is on NHL, our results could have substantial impact in the treatment of NCSLC. Lung cancer is the most common cause of cancer-death world- wide world [48, 49] in both men and women. NSCLC represents ~85% of all lung cancers. Approximately 2/3 of the patients have advanced or metastatic disease at the time of initial presentation [50]. Survival rates are 2- 20% depending on stage [51, 52]. Current chemotherapy bears significant toxicity. Checkpoint inhibition has revolutionized oncology, but up to two thirds of NSCLC patients fail to respond or eventually relapse. This proposal lays the groundwork for development of new, effective, and non-toxic treatment approaches for NHL and NSCLC , which are directly applicable to the VA patient population.